Toxicology and Risk Assessment

List of Contributors xv

Short CVs of Authors xix

Preface xxix

Dedication xxxi

List of Abbreviations xxxiii

1 Introduction to the Discipline of Toxicology 1
Helmut Greim and Robert Snyder

1.1 Introduction 1

1.2 The Risk Assessment Process 2

1.2.1 Hazard Identification 2

1.2.2 Dose Response and Toxic Potency 3

1.2.3 Exposure Assessment 4

1.2.4 Risk Characterization 6

1.3 Toxicological Evaluation of New and Existing Chemicals 6

1.3.1 General Requirements for Hazard Identification and Risk Assessment 7

1.3.2 General Approach for Hazard Identification and Risk Assessment (for details see Chapter 2.1) 12

1.3.3 Toxicological Issues related to Specific Chemical Classes 13

1.3.4 Existing Chemicals 14

1.3.5 Test Guidelines (Chapter 4.1) 14

1.3.6 Alternatives to Animal Experiments (Chapter 4.5) 15

1.3.7 Evaluation of Mixtures (Chapter 2.7) 15

1.3.8 Evaluation of Uncertainties 16

1.3.9 The Precautionary Principle 16

1.3.10 The TTC Concept 17

1.3.11 Classification and Labeling of Chemicals 17

1.4 Summary 18

2 Principles in Toxicology 21

2.1 General Concepts of Human Health Risk Assessment 21
Paul T.C. Harrison, Philip Holmes, and Ruth Bevan

2.1.1 Introduction 21

2.1.2 Principles of Risk Assessment 21

2.1.3 Application of Risk Assessment in Setting Exposure Standards and Limits 30

2.1.4 The Wider Importance of Risk Assessment 32

2.1.5 Summary 32

2.2 Toxicokinetics 34
Johannes G. Filser

2.2.1 Definition and Purpose 34

2.2.2 Absorption, Distribution, and Elimination 35

2.2.3 Toxicokinetic Models 47

2.2.4 Summary 61

2.3 Biotransformation of Xenobiotics 61
Wolfgang Dekant

2.3.1 Introduction 61

2.3.2 Phase I Reactions 64

2.3.3 Phase II Reactions 74

2.3.4 Factors that Influence the Biotransformation of Xenobiotics 80

2.3.5 Role of Bioactivation in Toxicity 87

2.3.6 Interactions of Reactive Intermediates formed during the Biotransformation 90

2.3.7 Summary 94

2.4 Cytotoxicity 98
Daniel Dietrich

2.4.1 Introduction 98

2.4.2 The Cell 102

2.4.3 Cellular Targets of Toxins 106

2.4.4 Mechanisms underlying Cell Death 115

2.4.5 Summary 120

2.5 Toxicogenetics 122
Lesley A. Stanley

2.5.1 Introduction 122

2.5.2 Toxicogenetics and Toxicogenomics 123

2.5.3 Genotype and Phenotype 123

2.5.4 The Role of Xenobiotic-metabolising Polymorphisms in Susceptibility to Toxic Agents 127

2.5.5 Study Numbers and Effect Size 135

2.5.6 Summary 139

2.6 Receptor-mediated Mechanisms 140
Jens Schlossmann and Franz Hofmann

2.6.1 Introduction 140

2.6.2 Ligand-Receptor Interactions 141

2.6.3 Biological Consequences of Ligand-Receptor Interactions 142

2.6.4 Receptor Signal Transduction 144

2.6.5 Summary 147

2.7 Mixtures and Combinations of Chemicals 148
Hermann Bolt

2.7.1 Introduction 148

2.7.2 Types of Mixed Exposures 148

2.7.3 Types of Joint Actions and their Role in Safety Evaluation 149

2.7.4 Role in Safety Evaluation 151

2.7.5 Summary 158

2.8 Chemical Carcinogenesis: Genotoxic and Non-Genotoxic Mechanisms 159
Thomas Efferth and Bernd Kaina

2.8.1 Introduction 159

2.8.2 Mechanisms of DNA Damage, Repair, and Carcinogenesis 160

2.8.3 Cancer Development 171

2.8.4 Non-Genotoxic Mechanisms of Carcinogenesis 181

2.8.5 Implications of Initiation and Promotion for Risk Assessment 184

2.8.6 Summary 185

2.9 Threshold Effects for Genotoxic Carcinogens 186
Helmut Greim

2.9.1 Introduction 186

2.9.2 Development of Cancer due to Genotoxic Carcinogens 187

2.9.3 Cellular Reaction to DNA Damage 187

2.9.4 Examples of Dose-dependent Reactions in Cases of Genotoxicity 193

2.9.5 Summary 193

2.10 Reproductive Toxicology 195
Horst Spielmann

2.10.1 Introduction 195

2.10.2 Characteristics of Reproductive Toxicology 196

2.10.3 Adverse Effects on Female and Male Fertility 197

2.10.4 International Test Methods in the Field of Reproductive Toxicology 199

2.10.5 Pre- and Postnatal Toxicology 201

2.10.6 Effects of Drugs and other Chemicals on Lactation 207

2.10.7 Endocrine Disrupters 208

2.10.8 Summary 208

2.11 Ecotoxicology: More than Wildlife Toxicology 209
Peter Calow and Valery E. Forbes

2.11.1 Introduction 209

2.11.2 Protection Targets 210

2.11.3 Necessary Information 211

2.11.4 Risk Assessment 216

2.11.5 Fast-track Approaches 217

2.11.6 Summary 218

3 Organ Toxicology 221

3.1 The Gastrointestinal Tract 221
Michael Schwenk

3.1.1 Introduction 221

3.1.2 Structure and Function 221

3.1.3 Fate of Xenobiotics in the GI Tract 223

3.1.4 Toxicology 226

3.1.5 Summary 231

3.2 The Liver 231
Jan G. Hengstler

3.2.1 Introduction 231

3.2.2 Structure and Function 232

3.2.3 Toxicology 237

3.2.4 Myths of the Liver 247

3.2.5 Summary 248

3.3 The Respiratory System 248
Florian Schulz

3.3.1 Introduction 248

3.3.2 Structure 249

3.3.3 Function 252

3.3.4 Protective Systems 254

3.3.5 The Respiratory Tract as a Target for Toxicity 256

3.3.6 Respiratory Allergy and Asthma 261

3.3.7 Lung Cancer 262

3.3.8 Test Systems to Detect the Toxic Effects of Inhaled Materials 263

3.3.9 Summary 263

3.4 The Nervous System 264
Gunter P. Eckert and Walter E. Mueller

3.4.1 Structure and Function of the Nervous System 264

3.4.2 The Nervous System Site of Attack for Toxins 273

3.4.3 Clinical Signs and Symptoms induced by Neurotoxins 279

3.4.4 Summary 281

3.5 Behavioral Neurotoxicology 283
Andreas Seeber

3.5.1 Introduction 283

3.5.2 Exposure Assessment 283

3.5.3 Methods 284

3.5.4 Neurobehavioral Effects in Humans 291

3.5.5 Summary 295

3.6 The Skin 296
Brunhilde Bloemeke

3.6.1 Structure 296

3.6.2 Function 298

3.6.3 Toxicology of the Skin and the Anterior Segment of the Eye 300

3.6.4 Summary 309

3.7 Kidney and Urinary Tract 311
Helmut Greim

3.7.1 Introduction 311

3.7.2 Anatomy and Function 311

3.7.3 Toxicology 313

3.7.4 Summary 319

3.8 The Hematopoietic System (Bone Marrow and Blood) 320
Robert Snyder

3.8.1 Introduction 320

3.8.2 Hematopoiesis 321

3.8.3 The Bone Marrow Niche 323

3.8.4 Toxicological Features of Circulating Blood Cells 323

3.8.5 Leucocytes (White Blood Cells) 326

3.8.6 Platelets (Thrombocytes) 328

3.8.7 Impairment of Bone Marrow Function 328

3.8.8 Mechanisms by which Chemicals can Induce Leukemia 330

3.8.9 Summary 330

3.9 The Immune System 331
Peter Griem

3.9.1 Introduction: the Innate and Specific Immune System 331

3.9.2 Antigen Recognition 333

3.9.3 Activation of T and B lymphocytes 334

3.9.4 Immunologic Tolerance 336

3.9.5 Sensitization and Allergy 337

3.9.6 Risk Assessment of Immunotoxic Effects 342

3.9.7 Chemical-induced Autoimmunity 345

3.9.8 General Immunostimulation by Chemicals 346

3.9.9 Chemical Immunosuppression 348

3.9.10 Summary 350

3.10 The Eye 351
Ines Lanzl

3.10.1 Introduction 351

3.10.2 Structure and Function of the Eye 351

3.10.3 Routes of Delivery of Xenobiotics to the Eye 354

3.10.4 Specific Toxicology of the Eye 355

3.10.5 Summary 363

3.11 The Cardiovascular System 364
Helmut Greim

3.11.1 Structure and Function 364

3.11.2 Toxicology 366

3.11.3 Summary 371

3.12 The Endocrine System 372
Gerlinde Schriever-Schwemmer

3.12.1 Introduction 372

3.12.2 Structure and Function 373

3.12.3 Foetal Development of the Hypothalamus-Pituitary-Gonad Axis 381

3.12.4 Testing of Sexual Function in Toxicology 383

3.12.5 Hazard Identification and Risk Assessment of Endocrine Disruptors 386

3.12.6 Summary 386

4 Methods in Toxicology 389

4.1 OECD Test Guidelines for Toxicity Tests in vivo 389
Ruediger Bartsch

4.1.1 Introduction 389

4.1.2 Requirements for in vivo Tests 390

4.1.3 Acute Toxicity 392

4.1.4 Skin and Eye Irritation 394

4.1.5 Skin Sensitization 397

4.1.6 Toxicity after Repeated Dosing 398

4.1.7 Reproductive Toxicity 401

4.1.8 Other Test Guidelines 406

4.1.9 Other Regulatory Bodies 407

4.1.10 Summary 407

4.2 Genotoxicity 408

4.2A In vitro Tests for Genotoxicity 408
Hans-Joerg Martus

4.2A.1 Introduction 408

4.2A.2 Bacterial Test Systems 409

4.2A.3 Test Systems employing Mammalian Cells 411

4.2A.4 Cell Transformation Assays 420

4.2A.5 Xenobiotic Metabolism 420

4.2A.6 Summary 421

4.2B Mutagenicity tests in vivo 422
Ilse-Dore Adler and Gerlinde Schriever-Schwemmer

4.2B.1 Introduction 422

4.2B.2 Chromosomal Mutations in Somatic Cells 424

4.2B.3 Gene Mutations in Somatic Cells 427

4.2B.4 Chromosome Mutations in Germ Cells 429

4.2B.5 Gene Mutations in Germ Cells 433

4.2B.6 Summary 435

4.3 Assessment of the Individual Exposure to Xenobiotics (Biomonitoring) 440
Thomas Goeen

4.3.1 Introduction 440

4.3.2 Prerequisites for Carrying Out Biomonitoring 442

4.3.3 Examples of Biomonitoring of Special Substance Groups or Special Biomonitoring Parameters 447

4.3.4 Summary 449

4.4 Epidemiology 450
Kurt Ulm

4.4.1 Introduction 450

4.4.2 Measures to Describe the Risk 450

4.4.3 Standardization 452

4.4.4 Types of Epidemiological Studies 454

4.4.5 Statistics 456

4.4.6 Meta-analysis 457

4.4.7 Bias, Confounding, Chance, Causality 459

4.4.8 Summary 460

4.5 Alternatives to Animal Testing 461
Thomas Hartung

4.5.1 Introduction 461

4.5.2 The Birth of Doubt in Animal Experiments 461

4.5.3 Early Successful Alternatives 463

4.5.4 The Replacement of Animal Tests is Possible 463

4.5.5 Validation of Alternative Methods: Animal Welfare must not Trump Patient and Consumer Safety 466

4.5.6 How Reliable are Animal Tests? 467

4.5.7 The Animal Test Ban for Cosmetics in Europe as an Engine of Change 467

4.5.8 "Toxicological Ignorance": the European REACH Program as a Driver for Alternative Methods 468

4.5.9 Outlook 469

4.5.10 Summary 471

4.6 Omics in Toxicology 472
Laura Suter-Dick

4.6.1 Introduction 472

4.6.2 Concept of Toxicogenomics 472

4.6.3 Technology Platforms 475

4.6.4 Bioinformatics and Biostatistics 480

4.6.5 Applications of Toxicogenomics 481

4.6.6 Summary 484

4.7 Introduction to the Statistical Analysis of Experimental Data 486
Gyoergy Csanady

4.7.1 Introduction 486

4.7.2 Descriptive Statistics 488

4.7.3 Error Propagation 491

4.7.4 Probability Distribution 492

4.7.5 Inferential Statistics 496

4.7.6 Regression Analysis 504

4.7.7 Probit Analysis 506

4.7.8 Experimental Designs 507

4.7.9 Statistical Software 508

4.7.10 Summary 509

4.8 Mathematical Models for Risk Extrapolation 510
Juergen Timm

4.8.1 Introduction 510

4.8.2 Basic Approach of Linear Extrapolation 512

4.8.3 Some Special Methods of Linear Extrapolation 514

4.8.4 Consideration of Time Aspects 515

4.8.5 Models of Carcinogenesis 518

4.8.6 Assumptions and Limits of Extrapolation in Mathematical Models 521

4.8.7 Summary 523

5 Regulatory Toxicology 525

5.1 Regulations on Chemical Substances in the European Union 525
Werner Lilienblum and Klaus-Michael Wollin

5.1.1 Introduction 525

5.1.2 Current Legislation in the EU 526

5.1.3 Risk Issues and Some Definitions in Terms of Chemical Substances 528

5.1.4 International Co-operation and Harmonization Supported and Implemented by the EU 531

5.1.5 EU Legislation on Chemical Substances and Their Uses 535

5.1.6 Legislation on Chemical Substances in the Environment 552

5.1.7 Summary 556

5.2 Regulations Regarding Chemicals and Radionuclides in the Environment, Workplace, Consumer Products, Foods, and Pharmaceuticals in the United States 557
Dennis J. Paustenbach

5.2.1 Introduction 557

5.2.2 Occupational Health Regulations 558

5.2.3 Food and Drug Regulations 561

5.2.4 Environmental Regulations 563

5.2.5 Consumer Product Regulations 568

5.2.6 Radionuclides Regulations 569

5.2.7 Governmental Agencies on Human Health 570

5.2.8 Centers for Disease Control 571

5.2.9 Litigation is Nearly as Effective as Regulation in the United States 571

5.2.10 Summary 572

5.3 The Concept of REACH 573
Joerg Lebsanft

5.3.1 Introduction 573

5.3.2 Historical Development 574

5.3.3 Substances, Mixtures and Articles 574

5.3.4 The Main Elements of REACH 575

5.3.5 Allocation of Responsibilities and Administration of REACH 580

5.3.6 Downstream Users 582

5.3.7 Outlook 583

5.3.8 Summary 583

6 Specific Toxicology 585

6.1 Persistent Halogenated Aromatic Hydrocarbons 585
Heidrun Greim and Karl K. Rozman

6.1.1 Introduction 585

6.1.2 Polychlorinated Dibenzodioxins and Dibenzofurans 586

6.1.3 Polychlorinated Biphenyls 588

6.1.4 Dichlorodiphenyltrichloroethane 589

6.1.5 Hexachlorobenzene 590

6.1.6 Physico-chemical Properties 591

6.1.7 Toxicity 592

6.1.8 Mechanisms of Action 600

6.1.9 Metabolism 603

6.1.10 Enzyme Induction 603

6.1.11 Kinetics 604

6.1.12 Summary 606

6.2 Metals 607
Andrea Hartwig and Gunnar Jahnke

6.2.1 General Aspects 607

6.2.2 The Importance of Bioavailability 608

6.2.3 Acute and Chronic Toxicity as well as Carcinogenicity 609

6.2.4 Toxicology of Selected Metal Compounds 611

6.2.5 Summary 624

6.3 Toxicology of Fibers and Particles 625
Paul J.A. Borm

6.3.1 Introduction 625

6.3.2 Particle Toxicology: Basic Concepts 626

6.3.3 Particle Properties 633

6.3.4 Nanoparticles: A Special Case? 636

6.3.5 Special Particle Effects 637

6.3.6 Summary 640

6.4 Principles of Nanomaterial Toxicology 641
Thomas Gebel

6.4.1 Introduction 641

6.4.2 Toxicology 643

6.4.3 Summary 648

6.5 Endocrine Active Compounds 649
Volker Strauss and Bennard van Ravenzwaay

6.5.1 Introduction 649

6.5.2 Thyroid Hormone Affecting Compounds 651

6.5.3 Sex Hormones 654

6.5.4 Low-dose, Non-monotonic Dose-effect Relation and Additive Effects 659

6.5.5 Summary 659

6.6 Assessment of Xenoestrogens and Xenoantiandrogens 661
Helmut Greim

6.6.1 Introduction 661

6.6.2 Modes of Action and Testing 662

6.6.3 A Weight of Evidence Approach and Future Improvements 666

6.6.4 Limited Evidence for Endocrine Disruption 667

6.6.5 Summary 667

6.7 Solvents 671
Wolfgang Dekant

6.7.1 Introduction 671

6.7.2 Toxicology of Selected Solvents 672

6.7.3 Hydrocarbons 677

6.7.4 Aliphatic Alcohols 680

6.7.5 Summary 685

6.8 Noxious Gases 686
Kai Kehe and Horst Thiermann

6.8.1 Introduction 686

6.8.2 Airborne Systemic Poisons 686

6.8.3 Respiratory Tract Irritants 692

6.8.4 Irritant Gases 694

6.8.5 Summary 698

6.9 Fragrance Materials 699
Anne Marie Api

6.9.1 Introduction 699

6.9.2 Evaluation of Toxicity 699

6.9.3 A Tiered Approach to the Risk Assessment of Fragrances 700

6.9.4 Summary 702

6.10 Pesticides 703
Roland Alfred Solecki and Vera Ritz

6.10.1 Introduction 703

6.10.2 Toxicity of Selected Pesticidal Active Substances 706

6.10.3 Fungicides 709

6.10.4 Insecticides 711

6.10.5 Substances of Biological Origin 713

6.10.6 Insect Growth Regulators 714

6.10.7 Other Pesticidal Active Substances 715

6.10.8 Regulatory Toxicology of Pesticidal Active Substances 716

6.10.9 Toxicological Endpoints 717

6.10.10 Classification and Cut-off Criteria 718

6.10.11 Human Health Risk Assessment 718

6.10.12 Summary 720

6.11 Polycyclic Aromatic Hydrocarbons 722
Heidrun Greim and Hermann Bolt

6.11.1 Introduction 722

6.11.2 Physico-chemical Properties 722

6.11.3 Occurrence in the Environment and in the Workplace 723

6.11.4 Toxicity 724

6.11.5 Mechanisms of Action 729

6.11.6 Evaluation by National and International Organisations 730

6.11.7 Toxicity Equivalency Factors for PAHs 731

6.11.8 Summary 732

6.12 Diesel Engine Emissions 733
Heidrun Greim

6.12.1 Introduction 733

6.12.2 Contents of Diesel Engine Emissions 734

6.12.3 Toxicokinetics 735

6.12.4 Toxicity 736

6.12.5 Mechanisms of the Carcinogenic Effects of Diesel Engine Emissions 738

6.12.6 The Exposure of Humans to Diesel Engine Emissions 740

6.12.7 Evaluation by International Organizations 740

6.12.8 Summary 741

6.13 Animal and Plant Toxins 742
Thomas Zielker

6.13.1 Introduction 742

6.13.2 Animal Toxins 742

6.13.3 Plant Toxins 751

6.13.4 Summary 759

Glossary of Important Terms in Toxicology 761

Index 769